The proposed studies are based on an original finding that mammalian cells with reduced or abrogated oncogenic potential can be regularly derived in cell culture by experimental development of resistance to actinomycin D and to other cancer chemotherapeutic agents. Drug resistant sublines are selected from cloned populations of syngeneic chemically induced mouse tumor cells and spontaneously transformed Chinese hamster cells. Resistance is also accompanied by phenotypic reversion to normal morphology and growth patterns in vitro and markedly reduced permeability to actinomycin D. Since accumulating evidence indicates that both drug resistance and altered growth properties are mediated by the cell membrane, investigations will be directed toward further elucidation of mechanisms of resistance and toward comparative analysis of membrane components (protein, glycoprotein, glycolipid) and their regulation, in malignant cells and nontumorigenic counterparts. New cell hybridization studies will be undertaken, utilizing chromosome banding methods, to determine whether a specific chromosome(s) is responsible for dominant expression of actinomycin D resistance in hybrid cells. Transplantation techniques will be employed, initially, to clarify whether reduced oncogenicity is due to increased immunogenicity or whether an alternative situation is (also) operative; maturation of malignant cells into intrinsically normal cells which have lost growth capacity in immunocompatible hosts.